Giuseppe Derosa

Effects of a Restricted Sleep Regimen on Ambulatory Blood Pressure Monitoring in Normotensive Subjects

The influence of sleep deprivation during the first part of the night on 24-h ambulatory blood pressure monitoring (ABPM) was studied in 18 normotensive subjects. They underwent two ABPM, one week apart: during the first, they slept from 11 PM to 7 AM, and during the second, from 2 AM to 7 AM. The main differences were observed at dawn, before awakening, when SBP and DBP significantly decreased (P < .01) in the restricted sleep regimen, and during the morning after the recovery sleep, when SBP and HR significantly increased (P < .05). The explanation for these findings is not obvious. We suppose that the decrease in SBP and DBP at dawn might be due to a reorganization of the sleep phases in the restricted sleep regimen, whereas the increase in SBP and HR after awakening might be due to a greater sympathetic activation, as though sleep deprivation was a stressful condition.

Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: A twelve-month, multicenter, double-blind, randomized, controlled, parallel-group trial

BACKGROUND Glimepiride is approved as monotherapy and in combination with metformin or with insulin, whereas the combination of glimepiride with other antihyperglycemic drugs is under investigation. OBJECTIVE The aim of this study was to assess the differential effect on glucose and lipid variables and tolerability of the combination of glimepiride plus pioglitazone or rosiglitazone in patients with type 2 diabetes mellitus (DM) and metabolic syndrome. METHODS This 12-month, multicenter, double-blind, randomized, controlled, parallel-group trial was conducted at 3 study sites in Italy. We assessed patients with type 2 DM (duration, > or =6 months) and with metabolic syndrome. All patients were required to have poor glycemic control with, or to have experienced > or =1 adverse effect (AE) with, diet and oral hypoglycemic agents such as sulfonylureas or metformin, both given up to the maximum tolerated dose. All patients received a fixed oral dose of glimepiride, 4 mg/d divided into 2 doses, self-administered for 12 months. Patients also were randomized to receive oral pioglitazone (15 mg once daily) (G + P group) or oral rosiglitazone (4 mg once daily) (G + R group), self-administered for 12 months. We assessed body mass index (BMI), glycemic control (glycosylated hemoglobin [HbA(1c)], fasting and postprandial plasma glucose and insulin levels [FPG, PPG, FPI, and PPI, respectively], and homeostasis model assessment index), lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides [TG]), and lipoprotein variables (apolipoprotein [apo] A-I and apo B) at baseline and at 3, 6, 9, and 12 months of treatment. Treatment tolerability was assessed at each study visit using a thorough interview of patients, and comparisons of clinical and laboratory values to baseline levels. RESULTS A total of 91 patients were enrolled in the study; 87 patients completed it (G + P group: 24 women, 21 men; mean [SD] age, 53 [6] years; G + R group: 20 women, 22 men; mean [SD] age, 54 [5] years). Patients in the G + P and G + R groups experienced significant increases in mean BMI at 12 months compared with baseline (4.92% and 6.17%, respectively; both, P < 0.05). The combination of glimepiride with pioglitazone or rosiglitazone significantly improved glycemic control in the study patients. At 12 months, we observed a 1.3% improvement in mean values for plasma HbA(1c) concentration (P < 0.01) 19.3% in FPG (P < 0.01), 16.3% in PPG (P < 0.01), 42.4% in FPI ), and 23.3% in PPI (P <0.05); no significant differences were found between treatment groups. Although the G + P group experienced a significant improvement at 12 months in almost all variables of lipid metabolism from baseline (TC, - 11%; LDL-C, -12%; HDL-C, 15%; and apo B, - 10.6% [all, P , 0.05]), the G + R group experienced a significant increase in mostly the lipid risk factors for cardiovascular disease (TC, 14.9%; LDL-C, 16.5%; TG, 17.9%; and apo B, 10.3% [all, P , 0.05]). Overall, no statistically significant changes in plasma aminotransferase activities were observed. Of the 87 patients who completed the study, 6.7% (3/45) of patients in the G + P group and 11.9% (5/42) of patients in the G + R group had transient, mild to moderate AEs that did not cause withdrawal from the trial. CONCLUSION In this study of patients with type 2 DM and metabolic syndrome who did not respond adequately to, or experienced AEs with, diet and either a sulfonylurea or metformin previously, the combination of glimepiride plus pioglitazone was associated with a significant improvement in lipid and lipoprotein variables, whereas the combination of glimepiride plus rosiglitazone appears to not have had any clinically significant effect on lipid metabolism.

Matrix Metalloproteinase-2, -9, and Tissue Inhibitor of Metalloproteinase-1 in Patients with Hypertension

There are conflicting data in the literature regarding the expression pattern of the vascular matrix metalloproteinase (MMP) system and their inhibitors (TIMPs) in human hypertension. The authors hypothesized that MMP-2, MMP-9, and TIMP-1 would be abnormal in hypertension, reflecting alterations in extracellular matrix (ECM) turnover. The authors measured plasma levels and activities of MMP-2, MMP-9, and TIMP-1 in 44 hypertensive patients and 44 controls. MMP-2 levels and activity were significantly higher in hypertensive group (p < .0001). Significant increase was also observed for MMP-9 level and activity (p < .0001) and for TIMP-1 (p < .0001) in hypertensive patients. Plasma levels and activities of MMP-2, MMP-9, and TIMP-1 are increased in hypertensive patients, which may reflect abnormal ECM metabolism.

Exenatide versus glibenclamide in patients with diabetes.

BACKGROUND Incretin-based therapies have provided additional options for the treatment of type 2 diabetes mellitus. The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state in patients with diabetes. METHODS One hundred twenty-eight patients with uncontrolled type 2 diabetes mellitus receiving therapy with metformin were randomized to take exenatide 5 microg twice a day or glibenclamide 2.5 mg three times a day and titrated to exenatide 10 microg twice a day or glibenclamide 5 mg three times a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR) index, homeostasis model assessment beta-cell function (HOMA-beta) index, plasma proinsulin (PPr), PPr/FPI ratio, resistin, retinol binding protein-4 (RBP-4), and high-sensitivity C-reactive protein (Hs-CRP) at baseline and after 3, 6, 9, and 12 months. RESULTS Body weight and BMI decreased with exenatide and increased with glibenclamide. A similar improvement of HbA(1c), FPG, and PPG was obtained in both groups, whereas FPI decreased with exenatide and increased with glibenclamide. The HOMA-IR index decreased and the HOMA-beta index increased with exenatide but not with glibenclamide. A decrease of PPr was reported in both groups, but only glibenclamide decreased the PPr/FPI ratio. Resistin and RBP-4 decreased with exenatide and increased with glibenclamide. A decrease of Hs-CRP was obtained with exenatide, whereas no variations were observed with glibenclamide. CONCLUSIONS Both exenatide and glibenclamide gave a similar improvement of glycemic control, but only exenatide gave improvements of insulin resistance and beta-cell function, giving also a decrease of body weight and of inflammatory state.

Effect of valsartan addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients

The aim of this study was to assess the effect of valsartan addition to amlodipine on ankle foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP), two objective measures of ankle oedema. After a 4-week placebo period, 80 grade 1–2 hypertensive patients (diastolic blood pressure (DBP)>90 mm Hg and <110 systolic blood pressure (SBP)>140 mm Hg) were randomized to amlodipine 10 mg or valsartan 160 mg or amlodipine 10 mg plus valsartan 160 mg for 6 weeks according to an open-label, blinded end point, crossover design. At the end of the placebo period and of each treatment period, blood pressure, AFV and PSTP were evaluated. AFV was measured using the principle of water displacement. PSTP was assessed connecting the subcutaneous pretibial interstitial environment with a water manometer. Both amlodipine and valsartan monotherapy significantly reduced SBP (−16.9 and –14.5 mm Hg, respectively, P<0.01 vs baseline), and DBP (−12.9 and −10.2 mm Hg, respectively, P<0.01 vs baseline) but the reduction was greater with the combination (−22.9 mm Hg for SBP, P<0.01 vs monotherapy; −16.8 mm Hg for DBP, P<0.01 vs monotherapy). Amlodipine monotherapy significantly increased both AFV (+23%, P<0.01 vs baseline) and PSTP (+75.5%, P<0.001 vs baseline) whereas valsartan monotherapy did not influence them. As compared to amlodipine alone, the combination produced a less marked increase in AFV (+6.8%, P<0.01 vs amlodipine) and PSTP (+23.2%, P<0.001 vs amlodipine). Ankle oedema was clinically evident in 24 patients with amlodipine and in six patients with the combination. These results suggest that angiotensin receptor blockers partially counteract the microcirculatory changes responsible for calcium channel blockers induced oedema formation.

Anti-obesity drugs: a review about their effects and their safety.

Introduction: Amphetamines, rimonabant and sibutramine licenses as anti-obesity drugs have been withdrawn because of their adverse effects. In fact, orlistat is the only available long-term treatment for obesity. Areas covered: The efficacy and safety of long-term drug therapy is very important in the management obesity; for this reason, the authors decided to conduct a review on the efficacy and safety of current, past and future pharmacotherapies for weight loss. Expert opinion: Orlistat is a good choice for the treatment of obesity, because of its safety on cardiovascular events and its positive effects on diabetic control, even if it is not as effective as rimonabant or sibutramine in reducing body weight. Regarding emerging anti-obesity therapies in diabetic people, we currently have drugs that have already been marketed including the glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide; other than improving glycemic control, they also suppress appetite reducing body weight. Moreover, some other drugs are currently in study such as tesofensine, phentermine + topiramate, bupropion + naltrexone and bupropion + zonisamide. Furthermore, several additional gut hormone-based treatments for obesity are under investigation in Phase II and III clinical trials, with particular focus on ghrelin, peptide YY, pancreatic polypeptide, amylin and oxyntomodulin.

Influence of losartan and atenolol on memory function in very elderly hypertensive patients

The aim of this study was to compare the effect of the beta-adrenergic blocker atenolol and the Angiotensin II type 1 (AT1) receptor antagonist losartan on cognitive function in very elderly hypertensive patients. A total of 120 mild to moderate essential hypertensive (DBP >90 and <105 mmHg) patients, aged 75–89 years, were studied. After a 4-week wash-out period on placebo, they were randomized to receive atenolol 50 mg or losartan 50 mg for 24 weeks according to a parallel arm design. At the end of the placebo period and of each active treatment period, BP was measured (by mercury sphygmomanometer, Korotkoff I and V) and cognitive function was evaluated through three different tests (word list memory, word list recall and word list fluency). Both atenolol and losartan were equally effective in reducing SBP (−22.1 and −23.1 mmHg, respectively, P< 0.01 vs baseline) and DBP (−10.3 and −11.2 mmHg, respectively, P< 0.01 vs baseline). Atenolol treatment did not induce significant changes in any test score, whereas losartan significantly increased the score of both the word list memory (+2.2, P<0.05 vs baseline) and the word list recall test (+2.1, P<0.05 vs baseline). The comparison between losartan and atenolol was significant (P<0.05) for both memory tests. These data suggest that in very elderly hypertensive patients, chronic AT1 receptor blockade by losartan could improve cognitive function, in particular immediate and delayed memory.

α-Glucosidase inhibitors and their use in clinical practice

Post-prandial hyperglycemia still remains a problem in the management of type 2 diabetes mellitus. Of all available anti-diabetic drugs, α-glucosidase inhibitors seem to be the most effective in reducing post-prandial hyperglycemia. We conducted a review analyzing the clinical efficacy and safety of α-glucosidase inhibitors, both alone and in combination with other anti-diabetic drugs, with respect to glycemic control, inflammation and atherosclerosis. α-Glucosidase inhibitors proved to be effective and safe both in monotherapy and as an add-on to other anti-diabetic drugs. Compared to miglitol and voglibose, acarbose seems to have some additive effects such as stabling carotid plaques, and reducing inflammation. Acarbose also proved to reverse impaired glucose tolerance to normal glucose tolerance.

Effects of sitagliptin or metformin added to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients.

The aim of the study was to compare the effects of the addition of sitagliptin or metformin to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state parameters. One hundred fifty-one patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >7.5%) in therapy with pioglitazone 30 mg/d were enrolled in this study. We randomized patients to take pioglitazone 30 mg plus sitagliptin 100 mg once a day, or pioglitazone 15 mg plus metformin 850 mg twice a day. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index, fasting plasma proinsulin (Pr), Pr/FPI ratio, adiponectin, resistin (R), tumor necrosis factor-alpha (TNF-alpha), and high-sensitivity C-reactive protein. A decrease of body weight and body mass index was observed with metformin, but not with sitagliptin, at the end of the study. We observed a comparable significant decrease of HbA(1c), FPG, and PPG and a significant increase of homeostasis model assessment beta-cell function index compared with baseline in both groups without any significant differences between the 2 groups. Fasting plasma insulin, fasting plasma Pr, Pr/FPI ratio, and HOMA-IR values were decreased in both groups even if the values obtained with metformin were significantly lower than the values obtained with sitagliptin. There were no significant variations of ADN, R, or TNF-alpha with sitagliptin, whereas a significant increase of ADN and a significant decrease of R and TNF-alpha values were recorded with metformin. A significant decrease of high-sensitivity C-reactive protein value was obtained in both groups without any significant differences between the 2 groups. There was a significant correlation between HOMA-IR decrease and ADN increase, and between HOMA-IR decrease and R and TNF-alpha decrease in pioglitazone plus metformin group after the treatment. The addition of both sitagliptin or metformin to pioglitazone gave an improvement of HbA(1c), FPG, and PPG; but metformin led also to a decrease of body weight and to a faster and better improvement of insulin resistance and inflammatory state parameters, even if sitagliptin produced a better protection of beta-cell function.

The effect of L-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus.

BACKGROUND A previous study has demonstrated that L-carnitine reduces plasma lipoprotein(a) (Lp[a]) levels in patients with hypercholesterolemia. OBJECTIVE To test a tolerable Lp(a)-reducing agent in diabetic patients, we assessed the effect of a dietary supplementation of L-carnitine on plasma lipid levels, particularly Lp(a), of patients with type 2 diabetes mellitus (DM) and hypercholesterolemia. METHODS In this 6-month, randomized, double-masked, placebo-controlled clinical trial, patients were enrolled, assessed, and followed up at the Diabetic and Metabolic Diseases Center of the Department of Internal Medicine and Therapeutics at the University of Pavia, Pavia, Italy. All study patients had newly diagnosed type 2 DM that was managed through dietary restriction alone throughout the study, as well as hypercholesterolemia. Patients were randomized to 1 of 2 groups. One group received L-carnitine, one 1-g tablet BID. The other group received a corresponding placebo. We assessed body mass index, fasting plasma glucose, postprandial plasma glucose, glycosylated hemoglobin, fasting plasma insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein (apo) A-I, apo B, and Lp(a) at baseline and at 1, 3, and 6 months of treatment. RESULTS This study included 94 patients. The treatment group included 24 men and 22 women (mean [SD] age, 52 [6] years). The placebo group included 23 men and 25 women (mean [SD] age, 50 [7] years). The baseline characteristics of the groups did not differ significantly. The mean (SD) body weight, height, and body mass index were 78.2 (5.8) kg, 1.70 (0.04) m, and 27.3 (2.5) kg/m(2), respectively, in the L-carnitine group and 77.6 (6.4) kg, 1.71 (0.05) m, and 26.8 (2.2) kg/m(2), respectively, in the placebo group. In the treatment group, Lp(a) was significantly reduced at 3 and 6 months compared with baseline (P < 0.05) and P < 0.01, respectively). We observed a significant improvement after 6 months (P < 0.05) in the Lp(a) value in patients taking L-carnitine compared with those taking placebo. Between-group differences in other variables did not reach a level of significance at months 3 and 6. No drug-related adverse events were reported or observed. CONCLUSION In this preliminary study, after 3 and 6 months, L-carnitine significantly lowered the plasma Lp(a) level compared with placebo in selected hypercholesterolemic patients with newly diagnosed type 2 DM.